tbuckley/cabot-search huggingface dataset:
Genomic profiling of rare undifferentiated sarcomatoid subtypes of pancreatic carcinomas for potential response to immunotherapy.
Authors: Erik Faber, Harris Krause, Phillip Walker, Peter Joel Hosein, Anthony Frank Shields, Heinz-Josef Lenz, Ajay Prakash, Sanjay Goel, Wolfgang Michael Korn, Matthew James Oberley, Claudio Luchini, Emil Lou
Journal: Journal of Clinical Oncology (2023)

741 Background: While pancreatic adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, the highly aggressive PDAC subtype of undifferentiated sarcomatoid carcinoma (USC) remains poorly characterized as it comprises only 2-3% of all PDAC histology. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy for USC, but the prevalence of established predictive biomarkers of response are largely unknown in this unique subpopulation. We identified PDAC USC patient samples from a large dataset and performed comprehensive genomic profiling to determine the prevalence of biomarkers associated with response to immunotherapy. Methods: PDAC USC patient samples (N=43) underwent central pathology review to confirm this diagnosis and were compared to non-USC PDAC patient samples (N=5562). Next-generation sequencing of DNA and RNA was performed at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142; Positive (+): ≥ 2+, ≥%5). A combination of IHC, NGS, and fragment analysis was used to assess deficient mismatch repair/microsatellite instability high (dMMR/MSI). High tumor mutational burden (TMB-High) was defined as ≥10 mutations/MB. Immune cell fractions of the tumor microenvironment were estimated by RNA deconvolution analysis using quanTIseq. Chi-square tests with Bonferoni correction for multiple comparisons were used to determine significance. Results: Among PDAC USC samples, KRAS (86% USC vs 90% non-USC, p = 0.31, q = 1), TP53 (86% vs 77%, p = 0.16, q = 1), and CDKN2A (18% vs 23%, p = 0.45, q = 1) were the most commonly mutated genes with a similar prevalence compared to non-USC histologies; however, KRAS was amplified more frequently (7% USC vs &lt;1% non-USC, q = 0.006). Furthermore, more USC tumors were PD-L1+ (63% vs 16%, q &lt; 0.001), while few USC samples were dMMR/MSI (2% USC vs 1% non-USC, p = 0.45, q = 1) or TMB-High (2% vs 2%, p = 0.89, q = 1). All USC tumors were deplete of lymphocytes, but many were differentially enriched (&gt;5%) with neutrophils (85% vs 57%, q = 0.03) or M2 macrophages (52% vs 28%, p = 0.006, q = 0.06). Conclusions: This work represents the largest molecular analysis of PDAC USC samples to date. Our analysis uncovered a different prevalence of amplified KRAS and PD-L1 expression in USC as compared to other PDAC histologies amidst an immune desert lacking lymphocytes in the USC tumor microenvironment. These findings provide evidence for further investigation into combination therapy of KRAS inhibitors with immune checkpoint inhibitors to target these immune-imbalanced microenvironment landscapes.
The association of the CARE Frailty Index with survival among older adults with pancreatic cancer.
Authors: Vinod Kumar, Grant Richard Williams, Smith Giri, Darryl Alan Outlaw, Mehmet Akce, Efrat Dotan, Bassel F. El-Rayes, Christian Harmon, Abigail Tucker, Sushanth Reddy, J. Bart Rose, Vikas Dudeja, Salila Hashmi
Journal: Journal of Clinical Oncology (2023)

699 Background: Outcomes of older adults with pancreatic cancer are highly variable with increased susceptibility to chemotherapy toxicities and inferior survival compared to younger patients. Determining which older adults are at higher risk for adverse outcomes remains a clinical challenge. We evaluated the association of a novel patient-reported geriatric assessment (GA)-based frailty index with survival among older adults with pancreatic cancer. Methods: Older adults (≥60y) referred for initial consultation at the UAB GI oncology clinic were prospectively enrolled in the Cancer and Aging Resilience Evaluation (CARE) registry. All patients underwent a patient-reported GA capturing multiple aging-related domains of health. The 44-item CARE frailty index (CARE-FI) based on the principles of deficit accumulation was utilized to determine frailty. The primary outcome was overall survival (OS) from the time of GA. Kaplan Meier method was used to estimate OS and comparisons between groups were by log-rank. A multivariate Cox regression model adjusted for age, sex, race, and cancer stage. Results: A total 254 older adults with pancreatic cancer were included; median age 70y, 52.4% male, 77% non-Hispanic white and 43.4% with stage IV disease. Overall, 40.1% (n=102) were frail, 26.0% (n=66) pre-frail and 33.9% (n=86) robust. No significant clinico-demographic differences across the 3 frailty groups were found. Differences in OS over two-year period was observed across the three frailty groups by the KM method ( p=0.008). In multivariate cox regression, frail status was associated with an increased risk of mortality (HR 1.9 [95% CI 1.19 – 2.98]; p=0.01) compared to robust status after adjustment for aforementioned confounders. Conclusions: The CARE-FI is a novel frailty index built on the principles of deficit accumulation using a patient-reported GA and is independently associated with survival among older adults with pancreatic cancer.[Table: see text]
CA125 kinetics as a potential biomarker of prognosis in nivolumab monotherapy for patients with advanced gastric cancer and peritoneal metastasis.
Authors: Takayuki Ando, Satoshi Yuki, Yosuke Kito, Akira Ueda, Iori Motoo, Ken Ito, Miho Sakumura, Yuko Ueda, Shinya Kajiura, Naokatsu Nakada, Koji Nakajima, Ayumu Hosokawa, Kazuaki Harada, Yasuyuki Kawamoto, Yoshito Komatsu, Ichiro Yasuda
Journal: Journal of Clinical Oncology (2023)

445 Background: The ascites develop in large proportion of patients during salvage-line chemotherapy for advanced gastric cancer (AGC). Serum CA125 is reported to be potential biomarker in peritoneal metastasis and associate with prognosis in first-line treatment for AGC. Therefore we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with third of later-line nivolumab monotherapy (Nivo). Methods: This multicenter retrospective study comprised AGC patients who received Nivo in third line or later setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before Nivo (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between CA125 kinetics and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 50 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=29) than those in non-elevated group. The median value of CA125 before Nivo was elevated according to ascites burden (none, 31.0 U/ml; mild, 49.4 U/ml; moderate/severe, 187.0 U/ml; p&lt;0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 3.2 vs. 9.4 months, p=0.035). After Nivo, first-time measure of CA125 was performed in a median of day 27. The median change of CA125 was correlated with ascites response (CR/PR, 0.04%/day; SD, 2.06%/day; PD, 4.17 %/day, p=0.013). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 2.4%/day (specificity 75%, sensitivity 70%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 1.4 vs 3.3 months, p=0.016). Conclusions: The serum CA125 before Nivo was associated with ascites burden. Further, CA125 kinetics after Nivo was associated with prognosis in AGC patients with peritoneal dissemination.
Effect of pancreatic enzyme replacement therapy (PERT) on body weight in advanced pancreatic cancer (APC).
Authors: Vincent J. Picozzi, Anas Najjar, Diala E Harb, Jens J Kort, Meg T. Mandelson
Journal: Journal of Clinical Oncology (2023)

698 Background: Malnutrition/cachexia is common in PC and is associated with multiple adverse patient (pt) outcomes. Current NCCN guidelines recommend PERT in PC pts with exocrine pancreatic insufficiency (EPI). However, little evidence exists regarding the impact of PERT on clinical outcomes in PC, especially APC. Data on impact of PERT use on change in body weight is presented here. Methods: Pts in this retrospective cohort study were identified from the Virginia Mason PC database. Eligibility requirements included: 1) no upfront resection 2) no prior PC therapy 3) pancreatic stool elastase 1&lt; 200 µg/g stool or documented clinical evidence of EPI at diagnosis 4) treatment at least to initial restaging event (8 weeks) 5) available data regarding PERT use/dosage. Weight/BMI was assessed at baseline and after 8 weeks on therapy. Two pt groups were compared; a) pts prescribed PERT for EPI at recommended package insert dose (≥ 500KU-2500/kg/meal for ≥ 3 meals/day) for ≥ 50% treatment period and b) pts who received no PERT. Pts on PERT at lower than recommended dose and /or &lt; 50% interval between 1st treatment and reassessment were excluded from analysis. Statistical significance was determined using the T-test for continuous variables, chi-squared for categorical variables. Results: 505 total pts were study eligible; 197 (39%) pts received PERT, 308 (61%) pts did not. Pt characteristics are shown. Despite a more adverse patient population with respect to weight loss, pts receiving PERT after 8 weeks experienced less change in weight (-0.36 kg vs -1.54 kg, P = 0.025) and change in BMI ( -0.64% vs -1.96., p= 0.026). Pts with cachexia experienced a similar outcome (-0.36% vs. -2.02 %, p= 0.026). No other pt characteristics achieved statistical significance. Conclusions: Despite a more adverse population with respect to weight loss at baseline, PERT usage prescribed per package insert guidance reduced wt loss/ change in BMI loss in APC over the 1st 8 weeks of therapy. This was also true in APC pts with cachexia. Further analysis of the impact of PERT therapy in APC with respect to treatment tolerability, and toxicity, quality of life and overall survival is warranted. [Table: see text]
CA125 kinetics as a potential biomarker for ascites progression during taxane plus ramucirumab therapy in patients with advanced gastric cancer.
Authors: Akira Ueda, Satoshi Yuki, Takayuki Ando, Iori Motoo, Ken Ito, Yosuke Kito, Miho Sakumura, Yuko Ueda, Shinya Kajiura, Naokatsu Nakada, Koji Nakajima, Ayumu Hosokawa, Kazuaki Harada, Yasuyuki Kawamoto, Yoshito Komatsu, Ichiro Yasuda
Journal: Journal of Clinical Oncology (2023)

437 Background: Ascites and peritoneal metastases are major interruptive factors in sequential chemotherapy for advanced gastric cancer (AGC), although there are no established markers that predict ascites burden during treatment. Therefore, we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with taxane plus ramucirumab (TAX/RAM). Methods: This multicenter retrospective study comprised AGC patients who received TAX/RAM in second or third line setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before TAX/RAM (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 73 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=31) than those in non-elevated group. The median value of CA125 before TAX/RAM was elevated according to ascites burden (none, 37.5 U/ml; mild, 57.9 U/ml; moderate/severe, 134.8 U/ml; p&lt;0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 8.2 vs. 14.6 months, p=0.0004). Baseline CA125 elevation and peritoneal metastasis were independent prognostic factors in multivariate analysis. After TAX/RAM, first-time measure of CA125 was performed in a median of day 28. The median change of CA125 was correlated with ascites response (CR/PR, -1.86%/day; SD, 0.28%/day; PD, 2.33 %/day, p&lt;0.001). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 0.0067%/day (specificity 74%, sensitivity 100%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 2.5 vs 6.1 months, p=0.0008). Conclusions: The serum CA125 before TAX/RAM was associated with ascites burden. Further, early change of CA125 after TAX/RAM was associated with prognosis in AGC patients with peritoneal dissemination. CA125 monitoring may be biomarker in determining timing of treatment change.
Using tumor growth rate to inform treatment efficacy in pancreatic adenocarcinoma: From the metastatic to the neoadjuvant setting.
Authors: Meredith LaRose, Celine Yeh, Mengxi Zhou, Keith Magnus Sigel, Gayle S. Jameson, Ruth Aroon White, Rachael A Safyan, Yvonne M. Saenger, Elizabeth Hecht, John A. Chabot, Stephen M. Schreibman, Antonio Tito Fojo, Gulam Abbas Manji, Daniel D. Von Hoff, Susan Elaine Bates
Journal: Journal of Clinical Oncology (2023)

726 Background: The development of new treatments in oncology is a long, costly, and, too often, unsuccessful process. Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials are needed. Methods: We used a mathematical model of tumor growth kinetics fit to serial radiographic tumor measurements or CA19-9 values to estimate rates of exponential tumor growth [g] and decay [d] during treatment for pancreatic ductal adenocarcinoma (PDAC). Results: We retrospectively collected and analyzed data from 2691 patients with stage III-IV PDAC who were enrolled in five clinical trials or were included in two large real-world data sets from Columbia University Irving Medical Center and Veterans Administration Medical Centers. Using log-rank comparison of Kaplan-Meier plots by quartile of g, we found that in patients with metastatic PDAC g correlates highly with overall (OS) and progression-free survival (PFS) (p&lt;0.001), with slower g associated with improved survival in this population. Pairwise comparisons showed significantly slower median g in the experimental arm versus control arm in the pivotal trials analyzed (p&lt;0.001). At the individual patient level, g was significantly faster for liver metastases as compared to primary pancreatic tumors and g consistently increased towards the end of therapy (often a threefold increase) suggesting development of chemoresistance. In addition to utility in the metastatic setting, a pilot analysis of data from a prospective study of patients treated with gemcitabine + docetaxel + capecitabine (GTX) in the neoadjuvant setting suggests that the emergence of a detectable g during neoadjuvant therapy may portend worse OS following surgery though sample size was small (n=45, median OS with detectable g 13.6 m v 33.1 without detectable g, p =0.35). Conclusions: We applied a tumor growth model to the data of over 2500 patients with PDAC and showed that g is inversely associated with survival in this population. Given the strong association between g and survival, g could be useful in clinical trials as an informative endpoint to expedite the assessment of novel therapies for the treatment of PDAC. Furthermore, g offers valuable patient-level data, including trends in resistance and variations in growth rate by metastatic disease site We plan to evaluate whether the emergence of g during neoadjuvant therapy should be considered a prompt to change treatment regimens.
Sonoporation for disrupting the pancreatic cancer microenvironment to enhance chemotherapy delivery and improve outcomes.
Authors: James Posey, Priscilla Machado, John R. Eisenbrey, Babar Bashir, Patrick Johnston Mille, Atrayee Basu Mallick, Rajan Singla, Spiros Kotopoulis, Ingrid K. Nordaas, Audun M. Trelsgård, Tæraneh Jouleh, Georg Gjorgji Dimcevski, Odd-Helge Gilja, Flemming Forsberg
Journal: Journal of Clinical Oncology (2023)

TPS777 Background: Pancreatic ductal adenocarcinoma (PDAC) is 3% of cancers diagnosed in the United States and it is the fourth leading cause of cancer-related deaths. Hence, there is a considerable clinical need to develop innovative strategies for effective drug delivery and treatment. Sonoporation is a novel method that can enhance the therapeutic efficacy of co-administered chemotherapy by localized contrast-enhanced ultrasound imaging (CEUS) of gas-filled microbubbles (ultrasound contrast agent UCA), which temporarily changes tumor vascular microenvironment by increasing angiogenic vessel leakage through microstreaming, shockwaves and the activation of various intracellular signaling responses. Our Phase I clinical trial of sonoporation in 10 PDAC patients treated with Gemcitabine demonstrated no additional toxicity and an increase in median survival compared to 63 historical controls (8.9 vs 17.6 months; p = 0.011). Animal studies investigated 4 commercial UCAs under 2 different acoustic regimes and established the optimal UCA (Sonazoid, GE Healthcare, Oslo, Norway) as well as acoustic settings for sonoporation of PDAC. Methods: This Phase II clinical trial aims to improve standard of care (SoC) chemotherapy treatment by adding sonoporation (i.e., augmenting the SoC treatment with CEUS and microbubbles). Two sites (one in USA and one in Norway) will enroll 120 subjects with PDAC stage III or IIV prior to starting SoC chemotherapy. Exclusion criteria include known allergies to the UCA. The primary objective is to evaluate the safety and therapeutic efficacy of sonoporation on PDAC SoC treatment based on local progression-free and overall survival. Two groups: SoC chemotherapy or SoC chemotherapy followed by sonoporation. The optimal CEUS and microbubble conditions will be applied to a single PDAC tumor imaged by ultrasound. Treatment delivered day of SoC chemotherapeutic treatment for PDAC when the concentration of drugs is maximum. Gehan-Breslow-Wilcoxon test and Log-rank test will be used to compare survival. All clinical variables (e.g., concomitant imaging results, blood tests, etc.) will also be compared between groups with and without sonoporation. Clinical trial information: NCT04821284 .
Comparison of anti–PD-L1 with anti–PD-1 antibodies in the combination of HAIC and lenvatinib for the treatment of unresectable hepatocellular carcinoma.
Authors: Shaohua Li, Jie Mei, Qiaoxuan Wang, Rongce Zhao, Lianghe Lu, Min Deng, Wenping Lin, Renguo Guan, Yuhua Wen, Lie Zheng, Wei Wei, Rongping Guo
Journal: Journal of Clinical Oncology (2023)

509 Background: Previous study showed the combination of hepatic artery infusion chemotherapy (HAIC), Lenvatinib and immune checkpoint inhibitors (ICIs) makes better overall response rate (ORR) as well as survival benefit than pure systematic treatment for unresectable hepatocellular carcinoma (uHCC). But how to choose different ICIs remains unclear. This study aimed to compare the efficacy and safety of anti-PD-1/PD-L1 antibodies combined with HAIC and Lenvatinib. Methods: This study retrospectively included 184 patients with uHCC treated with HAIC+ Lenvatinib +PD-1/PD-L1 antibody from June 2019 to January 2022 in the liver surgery department of Sun Yat-sen University Cancer Center. We used propensity score match (PSM) to screen and match 60 patients of HAIC+durvalumab+ Lenvatinib (HIL) versus 60 HAIC+PD-1+ Lenvatinib (HPL) to compare the efficacy and safety profile of these two groups. Results: The baseline is basically equilibrium between HIL and HPL group after matching. The median OS and PFS are not evaluable on the data cut-off date Sep 10, 2022. The ORR was higher in the HIL group than in the HPL group according to modified RECIST (mRECIST) (74.1% vs. 53.6%, p = 0.022) and RECIST 1.1 (60.3% vs. 41.1%, p = 0.040) respectively. In addition, 10 (17.2%) patients in the HIL group achieved complete response (CR) while 3 (5.4%) in the HPL group according to mRECIST. The results of subgroup analyses suggested that HIL approach could bring more survival benefits than HPL approach for patients with tumor smaller than 10cm and bilateral liver involvement. The incidence of grades 3 or 4 adverse events (AEs) was 10.0% and 18.3% with HIL and HPL group, respectively. Conclusions: Anti-PD-L1 antibody seems to be a better companion in the combination therapy of HAIC+ICIs+Lenvatinib than anti-PD-1 antibody for higher ORR and lower incidence of severe AEs. Further prospective study including larger population of patients is required.[Table: see text]
Feasibility and dynamics of preoperative circulating tumor DNA in patients with gastroesophageal cancer receiving preoperative treatment.
Authors: Lei Deng, Donna Olewniczak, Muhammad Awidi, Shruti Sharma, Charuta Palsuledesai, Adham A Jurdi, Minetta C. Liu, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2023)

436 Background: Tumor-informed circulating tumor DNA (ctDNA) testing has shown high sensitivity and specificity for detecting molecular residual disease across solid tumors. However, the requirement of high-quality tissue specimens for upfront sequencing and designing of personalized ctDNA assays can be challenging using preoperative biopsy samples. There is a paucity of data on the feasibility of testing in preop tissue specimens in patients (pts) with gastroesophageal cancer (GEC) as well as its preop dynamics. Methods: We prospectively enrolled pts with locally advanced esophageal, gastroesophageal junctional (GEJ), or gastric cancer who were to receive preop treatment and surgery between 11/2021 and 07/2022. Tumor tissue was analyzed with next-generation sequencing to design a personalized, tumor-informed multiplex PCR assay (Signatera bespoke mPCR NGS assay) for each patient. Peripheral blood was collected for ctDNA analysis at baseline (before preoperative treatment), every 4 weeks until surgery, after surgery (before adjuvant therapy), and then every 4 weeks for patients who received adjuvant chemotherapy or every 3 months for patients who received adjuvant immunotherapy or no active treatment. Results: A total of 17 pts were enrolled, of which 7 had esophageal, 5 had GEJ, and 5 had gastric cancer. Tumor tissues from 14 (82.4%) pts passed quality control (QC), of which 11 were preoperative biopsy samples and 3 were surgically resected tissue. All 14 pts had detectable baseline ctDNA prior to preoperative treatment, with a median at 1.05 mean tumor molecules per mL of plasma (MTM/mL). Of these, 92.8% (13/14) of pts achieved ctDNA clearance by a median of 5 weeks from the start of preoperative treatment. Four pts opted for endoscopy surveillance, of whom 1 pt had transient ctDNA clearance at week 10, but had positive ctDNA at week 14, which persisted as of week 26. Conclusions: In our cohort, locally advanced GEC were ctDNA shedders. Preoperative tumor-informed ctDNA testing was feasible. Further studies to evaluate correlation between ctDNA dynamics and response to treatment are warranted. [Table: see text]